10-121572176-A-T

Variant names:

• chr10-121572176-A-T
• rs4752569
• NM_022970.4:c.110-6472T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000141.5(FGFR2):​c.110-6472T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 145,462 control chromosomes in the GnomAD database, including 15,246 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.45 (15246 hom., cov: 25)
• Consequence: FGFR2 NM_000141.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.986
• Publications: 3 publications found

Genes affected

FGFR2 (HGNC:3689): (fibroblast growth factor receptor 2) The protein encoded by this gene is a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member is a high-affinity receptor for acidic, basic and/or keratinocyte growth factor, depending on the isoform. Mutations in this gene are associated with Crouzon syndrome, Pfeiffer syndrome, Craniosynostosis, Apert syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrata syndrome, Saethre-Chotzen syndrome, and syndromic craniosynostosis. Multiple alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jan 2009]

FGFR2 Gene-Disease associations (from GenCC):

• Apert syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, G2P, Orphanet
• Beare-Stevenson cutis gyrata syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, ClinGen, G2P
• bent bone dysplasia syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• Crouzon syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen, Ambry Genetics, G2P
• Jackson-Weiss syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• LADD syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Pfeiffer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics
• Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
• familial scaphocephaly syndrome, McGillivray type

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• Saethre-Chotzen syndrome

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Antley-Bixler syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• LADD syndrome

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen
• Pfeiffer syndrome type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Pfeiffer syndrome type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Pfeiffer syndrome type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.512 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000141.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR2	NM_022970.4	MANE Plus Clinical	c.110-6472T>A		intron	N/A	NP_075259.4	P21802-3
	FGFR2	NM_000141.5	MANE Select	c.110-6472T>A		intron	N/A	NP_000132.3	P21802-1
	FGFR2	NM_001441087.1		c.110-6472T>A		intron	N/A	NP_001428016.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR2	ENST00000457416.7	TSL:1 MANE Plus Clinical	c.110-6472T>A		intron	N/A	ENSP00000410294.2	P21802-3
	FGFR2	ENST00000358487.10	TSL:1 MANE Select	c.110-6472T>A		intron	N/A	ENSP00000351276.6	P21802-1
	FGFR2	ENST00000369056.5	TSL:1	c.110-6472T>A		intron	N/A	ENSP00000358052.1	P21802-17

Frequencies

GnomAD3 genomes AF: 0.447 AC: 65041 AN: 145392 Hom.: 15242 Cov.: 25

Gnomad AFR AF: 0.341

Gnomad AMI AF: 0.586

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.468

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.376

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.493

Gnomad NFE AF: 0.517

Gnomad OTH AF: 0.450

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.447 AC: 65049 AN: 145462 Hom.: 15246 Cov.: 25 AF XY: 0.443 AC XY: 31146 AN XY: 70354

African (AFR) AF: 0.341 AC: 13382 AN: 39246

American (AMR) AF: 0.489 AC: 7099 AN: 14508

Ashkenazi Jewish (ASJ) AF: 0.468 AC: 1611 AN: 3440

East Asian (EAS) AF: 0.265 AC: 1316 AN: 4962

South Asian (SAS) AF: 0.378 AC: 1741 AN: 4608

European-Finnish (FIN) AF: 0.441 AC: 3888 AN: 8826

Middle Eastern (MID) AF: 0.493 AC: 135 AN: 274

European-Non Finnish (NFE) AF: 0.517 AC: 34461 AN: 66696

Other (OTH) AF: 0.444 AC: 889 AN: 2002

Alfa AF: 0.444 Hom.: 1104

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.16
DANN	Benign	0.27
PhyloP100		-0.99
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4752569; hg19: chr10-123331690;